Clinical relevance and functional significance of cell-free microRNA-1260b expression profiles in infiltrative myxofibrosarcoma

Abstract

Infiltrative tumor growth into adjacent soft tissues is a major cause of the frequent recurrence and tumor-related death of myxofibrosarcoma (MFS), but no useful biomarkers reflecting tumor burden and infiltrative growth are available. While emerging evidence suggests a diagnostic and functional role of extracellular/circulating microRNA (miRNA) in various malignant diseases, their significance in MFS patients remains unknown. Global miRNA profiling identified four upregulated miRNAs in MFS patient sera and culture media of MFS cells. Among these, serum miR-1260b level was significantly upregulated in patient serum discriminating from healthy individuals and closely correlated with clinical status and tumor dynamics in MFS-bearing mice. In addition, high miR-1260b expression in serum was correlated with radiological tail-like patterns, characteristic of the infiltrative MFS. The extracellular miR-1260b was embedded in tumor-derived extracellular vesicles (EVs) and promoted cellular invasion of MFS through the downregulation of PCDH9 in the adjacent normal fibroblasts. Collectively, circulating miR-1260b expression may represent a novel diagnostic target for tumor monitoring of this highly aggressive sarcoma. Moreover, EV-miR-1260b could act as a transfer messenger to adjacent cells and mediate the infiltrative growth of MFS, providing new insights into the mechanism of infiltrative nature via crosstalk between tumor cells and their microenvironment. Lack of blood-based biomarkers is a major problem in the management of bone and soft tissue sarcomas (STSs). Detection of primary and/or recurrent tumors has generally relied on local symptoms and imaging modalities. Myxofibrosarcoma (MFS), one of the most common locally aggressive STSs 1,2 , is no exception. MFS comprises a spectrum of malignant fibroblastic lesions with variably myxoid stroma, pleomorphism, and a distinct curvilinear vascular pattern 3. In addition, it is clinically characterized by infiltrative growth into surrounding soft tissues 4-6. The infiltrative growth pattern is observed as a tail-like pattern on MRI and high correlations (87-100%) between radiological and pathological infiltration have been reported 7-9. Since the efficacy of radiotherapy and chemotherapy are limited in MFS, surgical resection with a wide margin is standard treatment 4-6. However, the local recurrence rate is high, ranging from 22% to 79%, even after wide resection 1,8,10,11 , and infiltrative growth is recognized as a primary risk factor for local recurrence and possibly distant metastasis 4-6,12-14. Approximately 30% of recurrent MFS progress to higher grade tumors, which exhibit increased metastatic potential and poor prognosis 15. However, there is no biomarker for monitoring tumor recurrence and the molecular mechanisms underlying the infiltrative nature of MFS remain unknown. Emerging evidence suggests that microRNAs (miRNAs) play a crucial role in tumor initiation, progression, and metastasis 16-18. miRNAs are small, non-coding RNA molecules consisting of approximat...

Sarcoma treatment in the era of molecular medicine

“…EVs secreted by dedifferentiated LPSs were also carriers of MDM2 DNA transferable to preadipocytes, which acquired oncogenic properties (e.g., impaired TP53 ) (Casadei et al , 2019). In addition, miR‐642a , miR‐1260b, and miR‐4286 were significantly higher in serum collected from myxofibrosarcoma patients compared with healthy controls, and miR‐1260b expression was associated with tumor burden and the infiltrative nature of sarcoma (Morita et al , 2020). Moreover, EVs derived from the plasma of GIST patients expressed activated KIT, which was undetectable in samples from healthy donors (Atay & Godwin, 2014).…”

Exosomes in the tumor microenvironment of sarcoma: from biological functions to clinical applications

“…Sarcoma cells release exosomes to alter fibroblast phenotype, thereby promoting tumor infiltrative and metastatic activities (Table 1 ). The malignant transformation of neighbouring normal fibroblasts contributed to sarcoma local invasion [ 67 , 68 ]. The surrounding fibroblasts absorbed exosomes from aggressive sarcoma cells and converted into a tumor-like phenotype [ 67 , 68 ].…”

“…The malignant transformation of neighbouring normal fibroblasts contributed to sarcoma local invasion [ 67 , 68 ]. The surrounding fibroblasts absorbed exosomes from aggressive sarcoma cells and converted into a tumor-like phenotype [ 67 , 68 ]. The resulting fibroblasts had enhanced proliferation and survival ability, and acquired capability to grow in an anchorage-independent manner [ 68 ].…”

“…The resulting fibroblasts had enhanced proliferation and survival ability, and acquired capability to grow in an anchorage-independent manner [ 68 ]. More importantly, these adjacent transformed fibroblasts facilitated tumor growth into surrounding soft tissues, and led to frequent recurrence of infiltrative myxofibrosarcoma [ 67 ]. In addition, the activation of distant fibroblasts is one of the early events in sarcoma metastasis.…”

“…The increased exosomal miR-195-3p could promote the proliferation and invasion of sarcoma cells, which further supported its significance in sarcoma detection [ 77 ]. Serum levels of exosomal miR-1260b were high in ten patients with infiltrative myxofibrosarcoma, which were more dominant in preoperative patients’ samples than those in postoperative [ 67 ]. The circulating exosomal miR-1260b levels were associated with tumor burden and the infiltrative ability of myxofibrosarcoma [ 67 ].…”